Feline animals, e.g. cats, are affected by various metabolic disorders. A number of metabolic disorders are known in feline animals, including hyperglycemia, insulin resistance, diabetes (such as diabetes mellitus type 1 or type 2, or pre-diabetes), hepatic lipidosis, obesity, hyperinsulinemia, impaired glucose tolerance, ketosis (in particular ketoacidosis), dyslipidemia, dysadipokinemia, obesity, subclinical inflammation or systemic inflammation, in particular low grade systemic inflammation, which also comprises adipose tissue, Syndrome X (metabolic syndrome), atherosclerosis and/or inflammation of the pancreas. Various correlations exist amongst these disorders. Among these disorders, in the cat, diabetes, in particular pre-diabetes and diabetes mellitus type 2, as well as hyperglycemia, insulin resistance, hepatic lipidosis, and obesity are gaining more and more importance. This can at least partially be ascribed to changing living and feeding behavior of companion animals during the last years.
Diabetes mellitus is characterized by disturbances in carbohydrate, protein and triglyceride metabolism based on a relative or absolute lack of insulin. It is a relatively common endocrinopathy in feline animals like the cat. The incidence for cats has increased about 5 to 12 fold in the last four decades to approximately 0.5 to 1.2%. Several risk factors have been identified: age, obesity, neutering and gender. Male, castrated, obese and old (>10 years) cats have probably the greatest risk to develop diabetes mellitus.
The current classification divides diabetes mellitus into three classes:
(1.) Type 1 which results from the loss of function of insulin secreting cells, e.g. by immunologic destruction of beta cells or insulin auto-antibodies (juvenile diabetes in humans);
(2.) Type 2 which results from a failure of the insulin stimulated cells to respond properly to insulin stimuli; it is also associated to e.g. amyloid accumulation in beta cells; type 2 usually develops during a long time of the so called pre-diabetes state; and(3.) Secondary diabetes mellitus which can due to diabetogenic drugs (e.g. long-acting glucosteroids, megestrol acetat, etc.) or to other primary diseases like pancreatitis, pancreas adenocarcinoma, cushing, hypo- or hyperthyroidism, growth-hormone producing tumors resulting in acromegaly.
In particular diabetes mellitus of type 2 is a growing problem for cat populations around the developed world. The lifestyle changes of cat owners are mirrored in their cats—increasingly they are kept indoors, with reduced activity levels, and fed a calorie-rich diet, leading to obesity and predisposition to diabetes mellitus type 2. As these trends continue, the incidence of diabetes mellitus in cats is sure to rise accordingly.
For the treatment of diabetes in humans, especially of type 2 diabetes mellitus, several oral antihyperglycemic drugs are approved. These drugs act e.g. by stimulating pancreatic insulin secretion in a glucose-independent or glucose-dependent manner (sulfonylurea/meglitinides, or DPP IV inhibitors, respectively), by enhancing tissue sensitivity to insulin (biguanides, thiazolidinediones), or by slowing postprandial intestinal glucose absorption (alpha-glucosidase inhibitors).
Other approaches have been contemplated for treating diabetes and reduce hyperglycemia in humans, including inhibition of the renal sodium-dependent glucose cotransporter SGLT2. SGLT2 in the kidney regulates glucose levels by mediating the reabsorption of glucose back into the plasma following filtration of the blood. SGLT2 inhibition thus induces glucosuria and may reduce blood glucose levels. For example, compound 1-cyano-2-(4-cyclopropyl-benzyl)-4-(ß-D-glucopyranos-1-yl)-benzene is described as an SGLT2 inhibitor in WO 2007/128749. A large variety of further SGLT2 inhibitors are also known. In WO 2011/117295, which is concerned with the medication of predominantly carnivorous non-human animals with dipeptidyl peptidase IV (DPP-IV) inhibitors, various SGLT2 inhibitors are recited amongst numerous other types of compounds in the context of combination therapies with DPP-IV inhibitors.
SGLT2 inhibition has not previously been contemplated for treatment of metabolic disorders in feline animals, such as cats. In feline animals, medications for metabolic disorders are far less advanced than in humans. Unfortunately, even if a treatment or prophylaxis is effective in humans, e.g., or other non-feline animals, it is not possible to conclude that the same approach will also be effective, safe and otherwise appropriate in a feline animal, such as a cat.
Feline animals differ significantly from humans or, e.g., dogs in respect of their metabolisms.
Being strict carnivores, felines are not well adapted to carbohydrates in the diet. For example feline livers show no activities of glucokinase (Tanaka et al., Vet Res Commun. 2005, 29(6):477-485). In most mammals, e.g. dogs or humans, hepatic glucokinase acts as a “glucose sensor” that permits hepatic metabolism to respond appropriately to changes in plasma glucose concentrations. Additionally, the release of insulin from a cat's pancreas appears to be less responsive to glucose as a stimulus as compared to most other species (Curry et al., Comp Biochem Physiol. 1982. 72A (2): 333-338).
Another adaptation to a strictly carnivorous diet relates to the utilization of protein and fat for energy production—i.e. gluconeogenesis. In an omnivore, gluconeogenesis occurs primarily in starvation situations. In contrast, in an obligate carnivore, such as the cat, gluconeogenesis appears to be constantly active in the liver, regardless of nutritional status and be postprandially even higher than in a fasted state (Hoenig et al. Am J Physiol, 2011, 301(6):R1798-1807, Verbrugghe et al., Crit Rev Food Sci Nutr. 2012; 52(2):172-182).
Consequently, the pathophysiology of feline metabolic disorders, and thus also their responses to medication of such disorders differs from other species.
As a diabetic complication e.g. vision problems and cataracts are commonly seen with diabetes mellitus in dogs, but are rarely found in feline animals.
Oral medications for diabetes that are known from human medicine such as glipizide (sulfonylurea) work in some small proportion of cats, but these drugs may be completely ineffective if the pancreas is not working. Worse, in some studies glipizide and other oral hypoglycemic drugs have been shown to generate side effects such as vomiting and icterus and to damage the pancreas even further leading to a reduction of the chances of remission from diabetes for cats. They have also been shown to cause liver damage. Even lower efficacies are reported for the other compound groups, i.e. meglitinides, biguanides, thiazolidinediones and α-glucosidase inhibitors (Palm C A et al., Vet Clin Small Anim 2013, 43: 407-415).
The gold-standard treatment of diabetic cats is currently considered to be injection of insulin. However, cats are notoriously unpredictable in their response to exogenous insulin. No single type of insulin is routinely effective in maintaining control of glycemia, even with twice-daily administration. Even with strict compliance from the owner control is often poor and secondary problems are common. Many owners find it impossible to achieve acceptable levels of compliance, as synchronization of food intake and insulin injection is impossible in the majority of cases. Ultimately many cats with diabetes mellitus are euthanized because of the disease.
The factors governing patient and owner compliance are also very different. In cats, oral administration, e.g., is yet more highly desirable than in humans.
A treatment that would allow better compliance and therefore better glycemic control than current insulin-based treatments would help to attenuate the progression of the disease and delay or prevent onset of complications in many animals.
Moreover, even when diabetic cats are treated aggressively with insulin and clinical remission is attained, this also does not necessarily normalize insulin secretion, pancreatic beta cell function and/or insulin resistance. Cats remain prone to a new onset of diabetes. It would be desirable to have a treatment of diabetes in feline animals which better improves, e.g., insulin resistance and pancreatic beta cell function (Reusch C E et al., Schweizer Archiv fuer Tierheilkunde 2011, 153811): 495-500).
Thus, there remains a particular need for effective, safe and otherwise appropriate treatments of metabolic disorders, including diabetes, in feline animals.